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U.S. Department of Health and Human Services

Animal & Veterinary

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NADA 126-050 APRALAN® 75 - supplemental approval (06/24/97)

I. GENERAL INFORMATION:

NADA126-050
Sponsor:Elanco Animal Health
A Division of Eli Lilly & Company
2001 West Main Street
Greenfield, IN 46140
Generic Name:apramycin sulfate
Trade Name:APRALAN® 75
Marketing Status:Over the Counter (OTC)
Effect of Supplement:Increases acceptable daily intake and safe residue concentration levels in edible tissues.

 

II. INDICATIONS FOR USE

For the control of porcine colibacillosis (weanling pig scours) caused by strains of E. coli sensitive to apramycin.

 

III. DOSAGE FORM, ROUTE OF ADMINISTRATION, AND RECOMMENDED DOSAGE

Refer to the original FOI Summary for NADA 126-050.

 

IV. HUMAN FOOD SAFETY

A. Toxicity Studies

The toxicity studies listed below are in addition to studies contained in the FOI Summaries for NADA 106-964 and 126-050.

  1. A One-Year Chronic Toxicity Study of Apramycin Administered Orally to Beagle Dogs

    1. Report Number: D-3088
    2. Study Completion: February 27, 1979
    3. Investigator:

      L.C. Howard
      Toxicology Division, Lilly Research Laboratories
      Division of Eli Lilly & Company
      Greenfield, Indiana 46140

    4. Substance and Dosage Form: Apramycin base was administered daily by the oral route.
    5. Species and Strain of Animal: Beagle dogs
    6. Number of Animals per Group: Animals were allocated 4/sex/dose.
    7. Levels and Duration of Dosing: Beagle dogs, between 86 and 142 days of age (males) and 86 to 115 days of age (females) at initiation of the study, were given doses of 0, 25, 50, or 100 mg apramycin activity per kilogram of body weight per day for one year.
    8. Route of Administration: Apramycin was given orally on a daily basis.
    9. Parameters: Study parameters included general physical condition and behavior, ophthalmoscopic examination, body weight, auditory responsiveness, hematology, bone marrow evaluation, clinical chemistry, urinalysis, absolute and relative organ weight, and gross and microscopic examination of tissues.
    10. Toxicities Observed: None
    11. No-Observed-Effect Level (NOEL): The NOEL for this study was 100 mg/kg/day.
    12. Conclusions: Statistically significant changes in hematology parameters were not considered related to apramycin administration because they were either isolated, not dose related, or were not observed at subsequent sampling times. Terminal myeloid:erythroid ratios were not significantly different from those of control dogs.

      Because of a lack of histopathological changes in selected organs, statistically significant changes in mean absolute and relative (to body weight) organ weights were not considered to be of toxicological importance. Additionally, when these tissues were compared relative to brain weights, significant differences were not observed. Statistical analysis of the parameters studied revealed no significant pathological effects of oral apramycin administration to beagle dogs at doses of 25, 50, or 100 mg/kg/day for one year.

  2. A Multi-Generation Reproduction Study with Apramycin in the Fischer 344 Rat

    1. Report Numbers: R-887, R-728, R-1318
    2. Study Completion: R-887, October 18, 1978; R-728, January 5, 1979; R-1318, June 11, 1979
    3. Investigator:

      L.C. Howard
      Toxicology Division, Lilly Research Laboratories
      Division of Eli Lilly and Company
      Greenfield, Indiana 46140

    4. Substance and Dosage Form: Apramycin was administered continuously in feed.
    5. Species and Strain of Animal: F1b offspring of Fischer 344 rats from the Multi-generation Reproduction Study
    6. Number of Animals per Group: Rats were allocated 25 rats/sex/dose for each parent generation.
    7. Levels and Duration of Dosing: Fischer rats were provided 0, 0.25, 0.5, or 1.0 percent apramycin in feed to determine the effect of apramycin on growth and reproduction through three generations. Based on feed intake and body weights, these levels translate to 0, 194, 388, and 785 mg/kg/day, respectively.
    8. Route of Administration: Apramycin was provided in feed.
    9. Parameters: Study parameters included diet assays, parental mortality, physical signs of toxicity, body weight, and food consumption.

      Reproduction Data and Progeny Observations: Fertility, liveborn litter size, gestation length and survival, progeny weight and sex. Progeny observations, gross internal examinations (all generations), and microscopic examinations (final generation).

      Reproduction Data and Fetal Observations, Teratology Segment: Fertility, live litter size, corpora lutea, implantation and resorption number, gestation length and survival, and fetal weight and sex. External, visceral and skeletal examinations of the fetuses were performed.

    10. Toxicities Observed: There were no treatment effects noted for any study parameters for the duration of the studies.
    11. No-Observed-Effect Level (NOEL): The NOEL for this study was 1.0% of the diet, or 785 mg/kg/day.
    12. Conclusions: Apramycin was well-tolerated with no significant observations for parental mortality, body weights, physical signs of toxicity, or treatment-related conditions. The reproductive capacity of the animals, including fertility, litter size, gestation length and survival, progeny survival and weight, and sex distribution, was unaffected. Apramycin at doses up to 785 mg/kg daily was not teratogenic and produced no adverse reproductive effects.
  3. A Chronic Toxicity-Oncogenicity Study in Fischer 344 Rats Maintained for Two Years on Diets Containing Apramycin

    1. Report Numbers: R478, R488
    2. Study Completion: May 30, 1980
    3. Investigator:

      L.C. Howard
      Toxicology Division, Lilly Research Laboratories
      Division of Eli Lilly & Company
      Greenfield, Indiana 46140

    4. Substance and Dosage Form: Apramycin was provided in feed.
    5. Species and Strain of Animal: Fischer 344 rats
    6. Number of Animals per Group: 50 rats/sex/dose were used.
    7. Levels and Duration of Dosing: Diets were fed for two years and contained 0, 0.25, 0.5, 1.0, and 5.0 percent apramycin, which provided time weighted averages of 0, 124, 245, 488, and 2,772 mg apramycin activity/kg for males and 0, 154, 301, 610, and 3,451 mg apramycin activity/kg for females.
    8. Route of Administration: Orally, via feed.
    9. Parameters: Study parameters included diet assays, survival, physical signs of toxicity, auditory response, body weight, food consumption, efficiency of food utilization, hematology, clinical chemistry, organ weights, and pathology.
    10. Toxicities Observed: Body weights were significantly decreased for rats in both sexes in the 5.0-percent-apramycin-treated group. The body weight effect was not associated with a detrimental effect on survival, nor was there evidence of chronic toxicity. Decreased organ weights for the 5.0-percent-apramycin-treated group were attributed to the significant reduction in growth. No other parameters were adversely affected by apramycin administration.
    11. No-Observed-Effect Level (NOEL): Based on the significant body weight reduction at 5.0 percent apramycin, the NOEL 1.0 percent apramycin (approximately 500 mg/kg body weight when averaged across both sexes).
    12. Conclusions: Because the rats in this study were progeny from rats utilized in the reproduction/teratology studies (R-887, R-728, R-1318), it is concluded that the exposure of rats to 1.0 percent apramycin during in utero development and up to 5.0 percent apramycin throughout lifetime produced significant weight gain impairment, but neither chronic toxicity nor carcinogenicity.
  4. A Chronic Toxicity-Carcinogenicity Study in B6C3F1 Mice Given Apramycin in the Diet for Two Years

    1. Report Numbers: M00679, M00779, M00780, M00880
    2. Study Completion: M00679, July 17, 1981; M00779, July 24, 1981 M00780, March 10, 1982; M00880, March 12, 1982
    3. Investigator:

      G.D. Williams
      Toxicology Division, Lilly Research Laboratories
      Division of Eli Lilly & Company
      Greenfield, Indiana 46140

    4. Substance and Dosage Form: Apramycin was administered in feed.
    5. Species and Strain of Animal: B6C3F1 mice
    6. Number of Animals per Group: 60 mice/sex/dose.
    7. Levels and Duration of Dosing: Mice were fed 0, 0.15, 0.5, 1.5, or 4.5 percent apramycin, which provided 0, 189, 623, 1,928, or 7,183 mg/kg for males and 0, 213, 668, 2,043, or 7,570 mg/kg for females, for two years.
    8. Route of Administration: Orally, via feed.
    9. Parameters: Study parameters included diet assays, survival, physical signs of toxicity, body weight, hematology, clinical chemistry, and organ weights.
    10. Toxicities Observed: Apramycin resulted in a decrease in both mean body weight and cumulative body weight gain at termination for the female mice fed 0.5, 1.5, and 4.5 percent apramycin, and for the male mice fed 4.5 percent apramycin. Mild increases in erythrocyte count, hemoglobin concentration, and packed cell volume were limited to mice fed diets containing 4.5 percent apramycin.

      Serum glucose concentrations were moderately decreased and urea nitrogen concentrations mildly increased in mice of both sexes fed diets containing 4.5 percent apramycin. Serum alkaline phosphatase was mildly elevated in female mice fed 0.5, 1.5, and 4.5 percent apramycin.

      Organ weights were consistent with the expected changes associated with a compound-related decrease in mean body weight. A punctate cytoplasmic basophilia involving renal tubular epithelium of mice fed 0.5 to 4.5 percent apramycin, but not 0.15 percent apramycin, occurred after two years on treatment. The incidence and grade of this finding were dose related and the lesion was more pronounced in females than males. The lesion was considered minimal and of no clinical significance.

      There was a marked reduction in the incidence of lymphosarcomas occurring in females fed diets containing 4.5 percent apramycin possibly due to their slower growth rate. No treatment related increase in neoplasia was observed.

    11. No-Observed-Effect Level (NOEL): The NOEL for this study was 0.15 percent of the diet (approximately 200 mg/kg).
    12. Conclusions: Apramycin fed to mice for two years at 0.15 percent of the diet produced no adverse effects. Levels of 0.5 to 4.5 percent produced lower weights and slight kidney histopathology.

B. Safe Concentration of total residues

  1. No-Observed-Effect Level (NOEL):

    The Safe Concentration of total residue was determined from the lowest NOEL in the most sensitive species from the various toxicology studies conducted. A summary of the studies which can be used in determination of the Acceptable Daily Intake (ADI) follows in Table 6.1.

    Table 6.1. Summary of ADI toxicology studies for apramycin
    Study TypeSpeciesDoses mg/kg/dayNOEL mg/kg/day
    One Year OralDog0, 25, 50, 100100
    Chronic Toxicity& OncogenicityRat0, 135, 275, 500, 3000*500
    OncogenicityMouse0, 200, 640, 2000, 7350*200
    Three-generation ReproductionRat0, 194, 388, 785785
    *Doses approximate based on apramycin concentration in feed, feed intake data and averaged across sexes.
    The one-year oral dog study was selected as the most appropriate study with the lowest NOEL for determining the acceptable daily intake (ADI). The NOEL for apramycin in that study was 100 mg/kg/day.
  2. Calculation of the Acceptable Daily Intake (ADI) of total residue of apramycin:

    Acceptable Daily Intake (ADI) = Lowest NOEL / Safety Factor

    A Safety Factor of 100 was used because the NOEL was from a chronic study.

    The lowest NOEL is 100 mg/kg, so ADI 

    = 100 mg/kg of body weight/day / 100

    = 1 mg/kg of body weight/day

    However, this NOEL-based ADI exceeds the 0.025 mg/kg body weight/day (1.5 mg/day) limit established in the CVM document Guidance: Microbiological Testing of Antimicrobial Drug Residues in Food (FDA/CVM, January 1996). That 1.5-mg/day level should produce no effects on human intestinal microflora. Therefore, in the absence of specific information on the effect of apramycin residues on human gut microflora, the Safe Concentrations were recalculated using the above equations and a weight-independent ADI of 1.5 mg/day and are summarized in Table 6.2.

  3. Calculations of Safe Concentrations (SC): The maximum ADI for total microbiologically-active residues of noncarcinogens is limited to 1.5 mg/person/day. The daily consumption values of edible tissues are approximated as 300 g (0.3 kg) for muscle, 100 g (0.1 kg) for liver, 50 g (0.05 kg) for fat/skin, and 50 g (0.05 kg) for kidney.

    Safe Concentration (SC) = Acceptable Daily Intake (ADI) / Consumption Value

    SC (muscle) = 1.5 mg/day / 0.3 kg/day = 5 mg/kg = 5 ppm

    SC (liver) = 1.5 mg/day / 0.1 kg/day = 15 mg/kg = 15 ppm

    SC (fat/skin) = 1.5 mg/day / 0.05 kg/day = 30 mg/kg = 30 ppm

    SC (kidney) = 1.5 mg/day / 0.05 kg/day = 30 mg/kg = 30 ppm

    Table 6.2. Safe Concentrations (SC) for total residues of apramycin in edible tissues using the revised food consumption factors
    Edible TissueAmount Consumed/DaySafe Concentration (SC)
    Muscle300 g5 ppm
    Liver100 g15 ppm
    Fat/Skin50 g30 ppm
    Kidney50 g30 ppm

C. Total Residue Depletion and Metabolism Studies

Refer to the original FOI Summary for NADA 126-050 for this information.

D. Comparative Metabolism

Refer to the original FOI Summary for NADA 126-050 for this information.

E. Tolerance for Residues

Refer to the original FOI Summary for NADA 126-050 for this information. The sponsor is not applying for a change in the marker residue concentration in swine kidney at this time. The current tolerance section in 21 CFR 556.52 is changed but retains wording for the existing tolerance in kidney as follows: "A tolerance of 0.1 ppm is established for parent apramycin (marker residue) in kidney (target tissue) of swine."

F. Withdrawal Time

Refer to the original FOI Summary for NADA 126-050. The sponsor is not applying for a change in the withdrawal period at this time. The current withdrawal period for apramycin use in swine is 28 days.

G. Regulatory Method

Refer to the original FOI Summary for NADA 126-050 for this information

 

V. AGENCY CONCLUSIONS

Following an evaluation of additional toxicology studies for apramycin in light of a current CVM guidance document, Guidance: Microbiological Testing of Antimicrobial Drug Residues in Food (FDA/CVM, January 1996), the Center has established a new acceptable daily intake (ADI) and concomitant safe concentrations for total residues in edible tissues. The ADI (25 mcg/kg/day) will be codified under 21 CFR 556.52, and the marker residue tolerance of 0.1 ppm for parent apramycin in kidney (target tissue) of swine will remain codified in that section. The previous tolerances for total residues will be deleted from section 556.52.

Under the Center's supplemental approval policy [21 CFR 514.106(b)(2)(xi)], this is a Category II supplement which required a re-evaluation of the tolerance according to current food safety guidance. This supplement did not require a re-evaluation of target animal safety or effectiveness data.

The agency has determined under 21 CFR 25.24 (d)(1)(i) that this action is of the type that does not individually or cumulatively have a significant effect on the human environment. Therefore, neither an environmental assessment nor an environmental impact statement is required.

APRALAN® patent numbers are U.S. 4,283,388 and 4,3333,919; expiring December 26, 1999, and September 12, 1999, respectively.

 

VIII. LABELING (Attached)

Copies of applicable labels may be obtained by writing to the:

Food and Drug Administration
Freedom of Information Staff (HFI-35)
5600 Fishers Lane
Rockville, MD 20857

Or requests may be sent via fax to: (301) 443-1726. If there are problems sending a fax, call (301) 443-2414.